Depression is a chronic illness with an estimated lifetime prevalence of 17%. The total annual cost of depression in the USA is estimated at $44 billion. As such, it represents a major health problem with a serious pharmacoeconomic impact (Griffiths, R. I. et al. Pharmacoeconomics 1999, 15(5), 495-505). Although the biochemical basis of depression is not completely elucidated, the most commonly accepted hypothesis states that depression occurs when monoaminergic neurotransmission in the brain is impaired. This theory is largely based on the observation that compounds that improve noradrenergic and/or serotoninergic neurotransmission often have beneficial effects in depression. Such an improvement in monoaminergic neurotransmission can be achieved in several ways. The biological effect of noradrenaline is terminated by two mechanisms: reuptake from the synaptic cleft into the neuron via the norepinephrine transporter (NET), and degradation by monoamine oxidase (MAO). For serotonin, reuptake in the neuron via the serotonin transporter (SERT) likewise limits its availability in the synaptic cleft.
Currently, clinical treatment of depression relies mainly on four types of drugs: 1) MAO inhibitors; 2) tricyclic antidepressants (TCA); 3) selective serotonin reuptake inhibitors (SSRI); and 4) other drugs such as reboxetine and venlafaxine. MAOs have long been used as second-line drugs because of their potentially dangerous side effects, and more recently, reversible MAO-A selective inhibitors with improved profiles have been described (Bonnet, U. CNS Drug Rev. 2002, 8(3), 283-308). TCAs such as amitryptiline display complex pharmacological activities. They inhibit reuptake of noradrenaline and serotonin via their respective transporters, but also have affinity at muscarinic and histamine H1 receptors. Thus, their efficacy in treating depression is counterbalanced by numerous unwanted side effects. The SSRIs, which represent the largest and most successful group of antidepressants, show a higher selectivity for the SERT than for the NET, although the exact affinity ratio varies from drug to drug. This class of drugs is characterized by a milder side-effect profile than the MAO-inhibitors or the TCAs. Other drugs have been described, such as reboxetine, which preferentially targets the NET, and venlafaxine, which has dual activity at the SERT and NET (Olver, J. S. et al. CNS Drugs 2001, 15(12), 941-954).
Although remarkable progress has been made in the treatment of depression, there remains opportunity for improvement. The delay between start of treatment and subjective improvement is a case in point. Most drugs do not cause an improvement in the Hamilton Rating Scale for Depression until after several weeks of treatment, potentially leaving the patient subject to severe mental anguish during this time. Currently available drugs have a limited response rate and in most clinical trials only about 30% of patients show clinical improvement (Menza, M. A. et al. J. Clin. Psych. 2000, 61(5), 378-381). Psychiatrists frequently have to evaluate several drugs for individual patients before a satisfactory therapeutic response is observed. Consequently there is a significant therapeutic need for drugs with a faster onset of action, improved side effect profiles and higher response ratio.
In order to appreciate the rationale for a combined SERT/H3 antagonist, it is necessary to understand the physiology of the histamine H3 receptor. This receptor was described in 1983 (Arrang, J.-M. et al. Nature (London) 1983, 302(5911), 832-837) as a presynaptic, auto-inhibitory receptor on histaminergic neurons with a characteristic pharmacology. Activation of the H3 receptor was shown to decrease the amount of histamine released from the nerve terminals and to inhibit the activity of histidine decarboxylase, the rate-limiting enzyme in the synthesis of histamine. The cloning and characterization of the human H3 receptor made it possible to explore its pharmacology (Lovenberg, T. W. et al. Molec. Pharmacol. 1999, 55(6), 1101-1107). It is now known that the H3 receptor is expressed on a variety of neurons and thus, when activated, decreases the release of a number of other neurotransmitters including noradrenaline, dopamine, and acetylcholine (Hill, S. J. et al. Pharmacol. Rev. 1997, 49(3), 253-278). For the purpose of this discussion, we will focus on its known effects on the release of the neurotransmitters involved in depression, noradrenaline and serotonin. Although the serotoninergic cell bodies are found in the dorsal raphe nucleus while the histaminergic cells are located in the tuberomammillary nucleus of the hypothalamus, both systems have extensive projections throughout the brain. In several regions, such as the suprachiasmatic nucleus (Laitinen, K. S. M. et al. Eur. J. Pharmacol. 1995, 285(2), 159-164) and striatum both neurotransmitters are present. It is known that activation of the H3 receptor leads to a decreased release of serotonin, for instance in rat cortex slices (Fink, K. et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 1990, 342(5), 513-519; Schlicker, E. et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 1988, 337(5), 588-590). Functional antagonists of the H3 receptor lead to an increased release of noradrenaline in the central (mouse cortex slices, Leurs, R. et al. J. Pharmacol. Exp. Ther. 1996, 276(3), 1009-1015; the rat hippocampus, Alvez-Rodrigues, A. et al. Brain Res. 1998, 788(1-2), 179-186) and peripheral nervous system (human myocardial nerves, Hatta, E. et al. J. Pharmacol. Exp. Ther. 1997, 283(2), 494-500; guinea-pig intestinal sympathetic nerves, Blandizzi, C. et al. Br. J. Pharmacol. 2000, 129(7), 1387-1396). However, there is little evidence that H3 receptor antagonists alone are capable of increasing serotonin levels in vivo to those required for antidepressant effects. Microdialysis studies of the effect of H3 antagonists on serotonin levels in the brain of live animals are lacking. There are sparse reports indicating that thioperamide, an H3 receptor antagonist, may have an antidepressant effect per se in the mouse or rat forced swim test (Lamberti, C. et al. Br. J. Pharmacol. 1998, 123(7), 1331-1336; Perez-Garcia, C. et al. Psychopharmacology 1999, 142(2), 215-220).
The rationale for combining H3 receptor blockade and SERT activity in one single molecule is the expectation that both mechanisms will contribute synergistically to enhanced concentrations of serotonin in the synaptic cleft. Antagonism at the H3 receptor will provide increased release of serotonin-containing vesicles into the synaptic cleft, and concomitant blockade of the SERT will decrease the neuronal reuptake of these neurotransmitter molecules. Thus, higher concentrations of serotonin will be achieved, leading to an enhanced therapeutic effect.
Among the prominent vegetative symptoms of depression are disturbed sleep and the daytime fatigue associated with it. Polysomnographic investigations have shown severe disturbances in the sleep architecture of depressed patients. Among the typical abnormalities observed are: discontinuous sleep, decreased slow-wave sleep, shorter latency to REM sleep and an increased intensity and duration of REM sleep (Riemann, D. et al. Neuropsychobiology 2002, 45(Suppl. 1), 7-12). It is believed that suppression of REM sleep is involved in antidepressant efficacy. This is illustrated by the dramatic success of overnight deprivation of (REM) sleep (Riemann et al. 2002). Another non-pharmacological treatment for depression, electroconvulsant therapy, likewise decreases REM sleep. Virtually all of the available antidepressant drugs, regardless of their neurochemical mechanism of action, suppress REM sleep, nefazodone (a 5-HT2A antagonist) being the exception (Sharpley, A. L., Cowen, P. J. Biol. Psych. 1995, 37(2), 85-98). Antidepressant drugs also affect slow-wave-sleep, although in a less clear manner. H3 antagonists share this REM-sleep suppressing property and one of the main biological effects of histamine H3 antagonists is to improve wakefulness. Administration of H3 antagonists has been shown to decrease REM and non-REM sleep in several animal species. For example, the H3 antagonist carboperamide induces waking in rats (Monti, J. M. et al. Neuropsychopharmacology 1996, 15(1), 31-35). Another H3 antagonist, thioperamide, decreased both REM and non-REM sleep in rats (Monti, J. M. et al. Eur. J. Pharmacol. 1991, 205(3), 283-287) and cats (Lin, J.-S. et al. Brain Res. 1990, 523(2), 325-330). It is of interest to note that although H3 antagonists promote wakefulness, they do so much less potently than amphetamine derivatives. They may thus be considered mild stimulants. The daytime correlate of disturbed sleep is fatigue. Indeed, fatigue and lethargy are prominent symptoms of depression, and there is considerable interest in the use of stimulants to augment antidepressant therapy (Menza et al., 2000). However, most of the available stimulants, like the amphetamine derivatives and methylphenidate, carry a considerable risk of abuse and are not ideal therapeutic choices. Modafinil, a wake-promoting compound of unknown mechanism with a lower addictive potential, is marketed for the treatment of narcolepsy. In a small series of patients it was shown that addition of a low dose of modafinil to traditional antidepressant therapy resulted in a faster onset of action. Fatigue was particularly responsive to this therapy, but the cognitive and physical subscales of the Hamilton Rating Scale for Depression also improved (Menza et al., 2000). The behavioral profile of H3 antagonists (suppression of sleep with no stimulation of locomotor activity and limited addictive potential) is much like that of modafinil. Therefore, a combined H3/SSRI compound would provide symptomatic relief for the fatigue during the first weeks of treatment, before the mood-elevating effect of the SSRI can be noticed.
Depression is also associated with a number of cognitive symptoms such as impaired memory and concentration difficulties. H3 antagonists have been shown to improve memory in a variety of memory tests, including the elevated plus maze in mice (Miyazaki, S. et al. Life Sci. 1995, 57(23), 2137-2144), a two-trial place recognition task (Orsetti, M. et al. Behav. Brain Res. 2001, 124(2), 235-242), the passive avoidance test in mice (Miyazaki, S. et al. Meth. Find. Exp. Clin. Pharmacol. 1995, 17(10), 653-658) and the radial maze in rats (Chen, Z. Acta Pharmacol. Sin. 2000, 21(10), 905-910). Also, in the spontaneously hypertensive rat, an animal model for the learning impairments in attention-deficit disorders, H3 antagonists were shown to improve memory (Fox, G. B. et al. Behav. Brain Res. 2002, 131(1-2), 151-161). Although no human studies are available, the evidence indicates that a combined SERT/H3 antagonist will provide additional benefit in combating the cognitive impairments associated with depression.
In summary, the combination of H3 receptor antagonism with SERT activity will result in the production of drugs with an improved antidepressant profile compared to an SSRI alone. These drugs will be especially efficacious in ameliorating the symptoms of fatigue, disturbed sleep and memory loss associated with depression.
The features and advantages of the invention are apparent to one of ordinary skill in the art. Based on this disclosure, including the summary, detailed description, background, examples, and claims, one of ordinary skill in the art will be able to make modifications and adaptations to various conditions and usages. Publications described herein are incorporated by reference in their entirety. In addition, U.S. Patent Appl. No. 60/637,173 is also incorporated by reference.